3beta-amino-18, 20-oxido-5alpha-pregnane and 5-pregnene compounds



J. LE MEN July 1s, 1967 s-AMINo-ls,zo-oxwo-a-PREGNANE AND s-PREGNENE COMPOUNDS Filed sept. 18, 1964 19 Sheets-Sheet 1 INVENTO:

JEAN LE MEN Y AGEA/r July 18, 1967 l 1.1.5 MEN 3,331,836

S-AMINO-IB,20-OXIDO-5d.-PREGNANE AND -PREGNENE COMPOUNDS Filed Sept. 18, 1964 19 Sheets-Sheet 2 i. I "x f I -52 D C A I -93 -j -t m 1 s# -S r [www /NVENTGR r JEAN LE MEN July 18, 1967 J. LE MEN 3,331,836

BMINO18,20-OXIDO5-PREGNANE AND EJ-PREGNENE COMPOUNDS v Filed Sept. 18, 1964 19 Sheets-Sheet 3 8200 2000 f Z400 2l00 1900 1700 i500 1800 H00 .900 700 3400 3000 f 2600 2200 2000 1800 i600 1400 1200 U00 900 WEA/Toa.-

JEAN Lt MEN marsanv J. LE MEN July 1s, 1967 55AMINO-l,20-OXIDO-5d-PREGNANE AND 5-PREGNENE COMPOUNDS 19 Sheets--Sheecl 4 Filed Sept. 18, 1964 gk v Sew mbo,

uns

gou

SN gwn @man /NVENTOR JEAN L E ME-N MAL m. RMLL,

J. LE MEN July 18, 1967 19 Sheets-Sheet 5 Filed Sept. 18, 1964 Q M t S m n w w m v n. on. S, a. il a QR SQ su SR m SS /NvE/vro/Q.-

JEAN LE MEN )l kcLMd/L/ AGLNI July 1s, 1967 J. Li: MEN 3,331,836

AMINO-lB,ZO-OXIDO-Sd-'PREGNANE AND 5PREGNENE COMPOUNDS UVv Filed Sept. 18, 1964 19 Sheets-Sheet 6 /Nve/vrok JEAN LE MEN 7 Mmhwwf July 1s, 1967v J. LE MEN 3,331,836

5BAMINO-18,20-OXIDO-5d-PREGNANE AND -PREGENE COMPOUNDS Filed Sept. 18, 1964 Y 19 Sheets-Sheet 7 900 800 700 l|||1||||||1||l1|||||11|l[-111linl NNW/MVM m Y v Il l2 18 INVENTOR JEAN LE ME/V B7 MAMMA AGENT July 18, 1967 J. LE MEN 3,331,836

5,8-AMIN-l8,20-OXIDO-51;-PREGNANE AND S-PREGNENE COMPOUNDS CM-I VvE/vrom JEAN LE MEN 8/ fm www A, @GENT Juy i8, 1967 .1. LE MEN 3,333,836

5AMINOl8,20OXIDO-5d.-PREGNANE AND .EJ-PREGNENE COMPOUNDS /A/vENToR JEAN LE MEN www AGEA/VT Juy 18, 967 J. LE MEN 3,331,836

-AMINO-l,20OXIDO-5l1-PREGNANE AND -PREGNENE COMPOUNDS Filed Sept. 18, 1964 19 Sheets-Sheet lO l I 1300 l 100 [200 1000 /NVENTOR JEAN LE MEN -uY 13, 967' J. LE MEN 3,333,836

55'AMINO-l8,20-OXIDO-5li-PREGNNE AND -PREGNENE COMPOUNDS Filed Sept. 18, 1964 19 Sl'neecs--Sheetv 11 mao l l l 7.900 i700 7500 i800 i600 I I I 2am 2400 2m@ 2600 2200 2000 I l l 3200 3400 3000 /N vENo/Q JEAN L5 MEN 57 91ML www July 18, 1967 J. LE MEN 3,331,836

B-AMINO-lS,20-OXIDO-5d-PREGNANE AND -PREGNENE COMPOUNDS Filed Sept. 18, 1964 19 Sheets-Sheet l?) 00 0 0 2700 i900 7700 i500 I300 H00 .900 700 c7000 28' 2600 2 0 2200 26100 i800 i600 1400 i200 i000 600 sena l/vve/vrofz JEAN LE MEN 7 WAWWMLV AGE/VT July 18, i967 J. LE MEN 3,331,836

SBAMINO-la,ZO-OXIDO--PREGNANE AND -PREGNENE COMPOUNDS IN VEN TOR JEA N LE MEN 57 MAMLQM,

Juy 18, ,1967 J, LE MEN 3,331,836

5-AMINO-l8,O-OXIDO-Sd-PREGNANB AND -PREGNENE COMPQUNDS JEAN LE NEN 7 ma www,

AGEN?" my i8, 1967 J. LE MEN '3,331,836

5AMINOl8,20-OXIDO-5d,-PREGNANE AND -PREGNENE COMPOUNDS /A/vE/VTOR JEAN LE MEN B7 ma mmm,

A65/vr@ 19 Sheets-Sheet 17 J. LE- MEN asv 5;@*AMINO-l8,20-OXIDO51-FREGNANE AND 5-PREGNENE COMPOUNDS Filed Sept. 18, 1964 my la, 1967 July 1s, 1967 J. LE MEN 3,331,836V

SB-AMINo-ls,20-ox1Do-5aPREGNANB ANDV 5-PREGNENE COMPOUNDS Filed Sept. 18, 1964 19 Sheets-Sheet 18 July 18, 1967 .1.1.5 MEN 3,3315836 5BAMINO18,20-OXIDO-5rL-PREGNANE AND -PREGNENE COMPOUNDS Filed sept. 18, 1964 19 shee'ts-sheet 19 SQ S m /NVE/VTGR JEAN LE NE/V AGENT United States Patent lice sexies@ Patented July 18, 1967 3,331,836 3-AMINO-18,20-0XIDO-5-PREGNANE AND -PREGNENE COMPOUNDS Jean Le Men, Limeil-Brevannes, France, assignor to Roger Bellon, Neuilly-sur-Seine, Seine, France Filed Sept. 18, 1964, Ser. No. 397,370 Claims priority, application Great Britain, Sept. 26, 1963, 38,027/ 63 18 Claims. (Cl. 260-239.55)

wherein R represents hydrogen or an alkyl group, preferably containing 1 to 4 carbon atoms, or an acyl group, preferably an alkanoyl group containing up to 4 carbon atoms, X and Y are hydrogen or together represent a single bond (so as to form a double bond between positions 5 and 6 of the steroid nucleus), one of Z `and Z is hydrogen and the other is hydroxy or acyloxy, preferably alkanoyloxy containing up to 4 carbon atoms, or Z and Z' together represent an oxo group, as well as the acid addition salts of these new derivatives.

These compounds are active anti-nammatory agents having a good therapeutic index, and can be used, for example, in the treatment and prevention of gastric ulcers. This activity has been demonstrated in the kaolin arthritis test. Experimental arthritis is produced by injecting 0.2 cc. of a sterile kaolin suspension into the tibiotarsal joint of the test animal. The diameter of the joint is then measured after a predetermined lapse of time. In the test, it was found that (20R)3-Nmethylamino la-hydroxyl 8,2O-oXido5-pregnene, (2DR) -S-N-methyl-N-acetylamino-l6aacetoxyl8,20 oxido-5 pregnene, and (ZUR)-B-N-methylamino-l-hydroxy-18,20-oxido- 5cc-Pregnana in doses of 20 to 50 Ing/kg. (by intraperitoneal injection) showed activities greater than cortisone, while not producing toxic effects at dosages below 200 to 300 mg./kg.

In Shays ulcer test, gastric ulcers are produced in the rat by ligature of the pylorus. An intraperitoneal dose of 50 mg./kg. of (ZGR)-3N-methyl-N-acetylamino16aacetoxy-l8,20-oxido-5-pregnene caused disappearance of the ulcers in 80% of the rats treated.

According to one embodiment of the invention, the new compounds are prepared by treating, with a mineral acid, e.g. hydrochloric acid, in a polar solvent, such as water or an alcohol miscible with water or ya mixture of the two, at a temperature between 60 and 100 C., a compound of the formula:

I OH CH2 l (iE-CH: l Z

Z CH3 wherein R, X, Y, Z and Z' are as hereinbefore defined. This reaction leads to a cyclisation giving an 18,20-oxido group, with reversal of the configuration of the ZO-c-arbon atom.

According to another embodiment of the invention, the compounds of Formula I in which R is alkyl are prepared by alkylating, e.g. rnethylating with formaldehyde and formic acid, a compound of the formula:

Where X, Y, Z and Z are as hereinbefore defined According to `another embodiment of the invention, the compounds of Formula I in which R is an acyl group are prepared by acylating, e.g. with acetic anhydride and pyridine to introduce an acetyl group, a compound of the formula:

NWCH;

/N H x where X, Y, Z and Z are as hereinbefore defined.

According to another embodiment of the invention, the compounds of Formula I in which X and Y are both hydrogen atoms are prepared by reducing by catalytic hydrogenation, eg. in the presence of Adams platinum catalyst, a corresponding compound in which X and Y together represent a single bond. 

1. A COMPOUND OF THE FORMULA: 